DESCRIPTION: Background Multiple myeloma (MM) is a devastating clonal disease of immunoglobulin (Ig) secreting plasma cells. The serum in MM patients typically includes high levels of monoclonal Ig, often referred to as the M protein. Although considerable advances have been made in the treatment of this disease, disease relapse remains a frequent occurrence and monitoring of minimum residual disease (MRD) following treatment is routine. However, measurement of MRD in MM post-treatment is currently performed by some combination of pathological examination of bone marrow plasma cells and examination of the level of M protein circulating in plasma. These techniques find a disease nadir but low levels of disease are often still present and this inevitably presents a future clinical challenge when the residual clonal population of plasma cells subsequently expands resulting in the need for further treatment. Additionally, bone marrow biopsy/aspiration is a costly and invasive procedure Objective Our objective is to develop a sensitive MRD assay that does not require a bone marrow biopsy and competes successfully with current bone marrow-based diagnostics for MRD. Methods The MRD diagnostic we propose only requires 5 l of serum from MM patients when first diagnosed and the monoclonal Ig is abundant in serum. We will analyze the Ig light chain protein by liquid chromatography mass spectrometry (LC-MS) and bioinformatically identify complementary determining region (CDR) tryptic peptides unique to each patient's plasma cell's Ig clone without genomic sequence information. MRD will be measured in subsequent venous blood samples by extracting Ig light chain from a venous blood sample and monitoring the level of CDR tryptic peptides identified previously by LC-MS. Preliminary results indicate this is a viable technique and successfully competes with current blood-based diagnostics with ~2,000x more sensitivity. We will optimize the LC-MS technique to compete successfully with bone marrow- based techniques for MRD eliminating the need for bone marrow biopsy/aspirations.